Genetic counseling: 1p36 Deletion Syndrome-2
1p36 Deletion Syndrome Introduction *Mental retardation affects 2-3% of the population and chromosome abnormalities account for about 20% of cases *Improved techniques in cytogenetics (FISH) have helped to identify submicroscopic deletions at the cytogenetic level *Syndrome is characterized by distinct facial features, mental retardation, and delayed growth *This condition is likely a contiguous gene deletion syndrome **There is no uniform region of deletion but rather a spectrum of different deletion sizes with a common minimal region of deletion overlap **Genotype/phenotype comparisons can help researchers to start to define a region in which to search for candidate genes for specific features Etiology of 1p36 deletion syndrome (monosomy 1p36) *Caused by deletion of the most distal (telomeric) light band of the short arm of chromosome 1 *Most clinical manifestations are probably caused by the absence of one copy of a dose-sensitive gene *Patients with a 1p36 deletion have different sized pieces of the chromosome missing and may result in phenotype variability **Mechanism causing chromosome breakage is unknown **Severity of associated disorders varies, but the physical features are very similar **Degree of MR and ability to acquire complex speech is somewhat dependent on deletion size *Most deletions affect the chromosome inherited from the mother (68%), but there doesn't seem to be differences in the clinical manifestations based on whether the deletion is on the paternal or maternal chromosome. *Those with paternally derived deletions tend to have larger deletions than those with maternally derived deletions Prevalence *Prevalence of this deletion is estimated to be 1 in 10,000 to as high as 1 in 5,000 (making it the most common terminal deletion) *Most cases result from sporadic deletions and are not inherited *1p36 deletion syndrome is usually diagnosed through recognition of the symptoms and characteristics as well as lab testing. **This is done using high-resolution chromosome analysis or FISH with a chromosome 1-specific subtelomeric probe. **The deletion often doesn't show up clearly with standard cytogenetic banding techniques. Characteristics *Children with 1p36 deletion syndrome are all unique individuals, but do have some common characteristics. *Distinct facial features including: **Large anterior fontanel (~100% of patients) **Small and pointed chin (~80%) **Flat nasal bridge (~65%) **Clinodactyly and/or short fifth finger (~64%) **Low-set ears, ear asymmetry (~59%) **Thickened ear helices (~53%) **Small head **Deep-set eyes (~50%) *Most patients have mental retardation *Most patients have delayed growth (~85%) and/or difficulty gaining weight **Some have difficulty with sucking and swallowing while others may not grow well even though they eat well. **Some older children may become obese. *Most young children with 1p36 deletion syndrome have delayed development. **They sit up, walk and talk later than typical children. *Speech is severely affected with many patients learning only a few words *Other medical problems: **Hypotony (which may explain delayed motor skills) (seen in ~92%) **Hearing loss (~56%) **Seizures (~72%) ***KCNAB2 is a voltage-gated K+ channel beta-subunit gene that has been localized to 1p36 and thought to be associated with the epilepsy phenotype of 1p36 **Eye/vision problems (~75%) **Hypothyroidism **Increased risk for neuroblastoma **Heart defects (which have included cardiomyopathy, ductus arteriosus, tetralogy of Fallot, VSD) **Orofacial clefting abnormalities ***SKI, a proto-oncogene located at distal 1p36.3 has been found to be deleted in a number of patients tested and may contribute to facial clefting seen in this syndrome ***SKI overexpression has suggested that the gene is involved in neural tube development and muscle differentiations. Recurrence Risk for next pregnancy *The majority of patients with 1p36 deletion syndrome are isolated cases resulting from a de novo deletion. There have been reports of patients with 1p36 deletion syndrome whose parents have a balanced translocation. *Parents should be tested for chromosomal rearrangements because about 6% of parents with an affected child have a balanced translocation *Translocation increases the chances of having another child with a 1p36 deletion. **If no translocation is found the chances of having another child with a 1p36 deletion are very small Prenatal Diagnosis *In 1999 a case was reported in which a 1p36 deletion in a fetus was detected when an amniocentesis was performed due to detection of multiple malformations on ultrasound *Another case was picked up prenatally because of the presence of elevated maternal serum alpha-fetoprotein (no abnormal sign seen on ultrasound) *Another was diagnosed prenatally because the mother was known to have a balanced translocation between the short arms of chromosome 1 and 20 that was picked up after their first child had inherited an unbalanced product. (no abnormal sign seen on ultrasound) Medical Treatment *Seizures can usually be controlled with medication *Medical interventions and feeding therapy may be needed to manage feeding issues *Early Intervention for developmental delay *Surgery may be necessary to correct heart defects, cleft lip, cleft palate if present *Physical examinations should involve palpating the abdomen for lumps which might be neuroblastomas *There are no clear indications on whether they should continue to be followed by a cardiologist or whether the cardiomyopathy is limited to a congenital form. Psychosocial Issues *Initially parents may experience denial about how severe the developmental delay and mental retardation will be *Blaming of self or partner may occur *Stress of having a child with developmental delays and mental retardation *Stress associated with having a child with serious medical problems especially if they have heart malformations or seizures *Time commitment involved with early intervention services (OT, PT, speech therapy) Patient Resources *Chromosome Deletion Outreach http://www.chromosomedisorder.org *MUMS http://www.netnet.net/mums/ References *Colmenares, C., et al. Loss of the SKI proto-oncogene in individuals affected with 1p36 deletion syndrome is predicted by strain-dependent defects in Ski -/- mice. Nature Genetics 30(1), 106-109, Jan 2002. *Faivre, L. et al. Prenatal Detection of a 1p36 Deletion in a Fetus with Multiple Malformations and a Review of the Literature. Prenatal Diagnosis. 19:49-53, 1999. *Heilstedt, H.A. et al. Loss of the Potassium Channel B-subunit gene, KCNAB2, Is Associated with Epilepsy in Patients with 1p36 Deletion Syndrome. Epilepsia. 42(9): 1103-1111, 2001. *Shaffer, L.G. and Heilstedt, H.A. Terminal Deletion of 1p36. The Lancet Supplement 358: 89, 2001. *Shapira, Stuart, et al. Chromosome 1p36 Deletions: The Clinical Phenotype and Molecular Characterization of a Common Newly Delineated Syndrome. American Journal of Human Genetics 61: 642-650, 1997. *Slavotinek, Anne, Lisa G. Shaffer, Stuart K Sharpira. Monosomy 1p36. Journal of Medical Genetics 36: 657-663, 1999. Notes The information for this outline was last updated in June of 2002. Material obtained under GFDL Licence from http://en.wikibooks.org/wiki/Handbook_of_Genetic_Counseling